Why are Hoogsteen base pairs energetically disfavored in A-RNA compared to B-DNA?
Why are Hoogsteen base pairs energetically disfavored in A-RNA compared to B-DNA?
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与 B-DNA 相比，为什么 A-RNA 中的 Hoogsteen 碱基对在能量上不受欢迎？
DOI：
10.1093/nar/gky885
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发表时间：
2018
影响因子：
14.9
通讯作者：
Al-Hashimi,HashimM
中科院分区：
文献类型：
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作者：
Rangadurai,Atul;Zhou,Huiqing;Merriman,DawnK;Meiser,Nathalie;Liu,Bei;Shi,Honglue;Szymanski,EricS;Al-Hashimi,HashimM
与B-DNA相比，A(Syn)-U/T和G(Syn)-C+Hoogsteen(HG)碱基对(Bps)在A-RNA中比Watson-Crick(WC)碱基对(Bps)更不受欢迎，原因尚不完全清楚。在这里，我们使用核磁共振光谱、光学熔融实验、分子动力学模拟和修饰核苷酸来确定导致A-RNA中HG BP失稳的因素。去掉A-RNA双链上的2‘-羟基并不能使HGBP相对WC稳定下来。相反，通过A-RNA中的凸起放松A-型几何结构，将在侧翼位置形成HG碱基的能量成本降低到B-DNA水平。对嘌呤-嘌呤汞错配的结构和热力学分析表明，与B-DNA相比，A型几何构型不利于合成嘌呤1.5-4千卡/摩尔，这是因为需要糖骨架重排来空间容纳合成碱。根据MD模拟，由于移动碱基在A-RNA中形成氢键比在B-DNA中形成氢键所需的能量成本更高，因此对嘌呤-嘧啶HG-BP的额外惩罚为3-4千卡/摩尔。这些结果为A-RNA和B-DNA双链之间的根本差异提供了见解，对它们如何应对损伤和转录后修饰具有重要意义。
A(syn)-U/T and G(syn)-C+Hoogsteen (HG) base pairs (bps) are energetically more disfavored relative to Watson–Crick (WC) bps in A-RNA as compared to B-DNA by >1 kcal/mol for reasons that are not fully understood. Here, we used NMR spectroscopy, optical melting experiments, molecular dynamics simulations and modified nucleotides to identify factors that contribute to this destabilization of HG bps in A-RNA. Removing the 2′-hydroxyl at single purine nucleotides in A-RNA duplexes did not stabilize HG bps relative to WC. In contrast, loosening the A-form geometry using a bulge in A-RNA reduced the energy cost of forming HG bps at the flanking sites to B-DNA levels. A structural and thermodynamic analysis of purine-purine HG mismatches reveals that compared to B-DNA, the A-form geometry disfavorssynpurines by 1.5–4 kcal/mol due to sugar-backbone rearrangements needed to sterically accommodate thesynbase. Based on MD simulations, an additional penalty of 3–4 kcal/mol applies for purine-pyrimidine HG bps due to the higher energetic cost associated with moving the bases to form hydrogen bonds in A-RNA versus B-DNA. These results provide insights into a fundamental difference between A-RNA and B-DNA duplexes with important implications for how they respond to damage and post-transcriptional modifications.